Neuro-Ophthalmic Presentation of Myelomatous Meningitis

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Neuro-Ophthalmic Presentation of Myelomatous Meningitis Andrew C. Thomson, BS, Mohammad Obadah Nakawah, MD, Subahari Raviskanthan, MBBS, Peter W. Mortensen, MD, Andrew G. Lee, MD R ecent advances in multiple myeloma (MM) treatments including immune and targeted therapies have increased patient survival rates and extramedullary disease. MM with central nervous system relapse (CNS-MM) is seen in less than 1% of MM cases (1). CNS-MM is a challenging disease with very poor prognosis and overall survival of less than 7 months (2,3). We report a rare case of myelomatous meningitis (MyM) who presented with rapid cognitive decline, gait dysfunction, and neuro-ophthalmic manifestations of bilateral optic disc edema, bilateral optic nerve sheath and cranial nerve enhancement on MRI, and a left relative afferent pupillary defect (RAPD). A 74-year-old Hispanic woman was admitted to our hospital with progressive gait instability, urinary incontinence, and cognitive decline. Her medical history was significant for primary open-angle glaucoma, Type 2 diabetes, peripheral neuropathy, hypothyroidism, dementia, and Immunoglobulin A kappa MM with high-risk cytogenetics that was managed with autologous stem-cell transplant 4 years ago and 10 mg oral lenalidomide maintenance therapy. Her medications included topical bimatoprost and brimonidine–timolol, insulin, carvedilol, levothyroxine, and rivastigmine. She did not smoke or drink alcohol. On examination, she was responsive to voice but unable to follow commands. Visual acuity could not be reliably assessed. Her pupils were isocoric and reactive with a left RAPD. External and slit-lamp examinations were normal. Intraocular pressure measured 27 mm Hg in the right eye and 29 mm Hg in the left eye. Dilated fundus examination McGovern Medical School at The University of Texas Health Science Center at Houston (ACT), Houston, Texas; Department of Neurology (MON), Houston Methodist Neurological Institute, Houston, Texas; Department of Ophthalmology (SR, PWM, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medicine, New York, New York; Department of Ophthalmology (AGL), University of Texas Medical Branch, Galveston, Texas; University of Texas MD Anderson Cancer Center (AGL), Houston, Texas; and Department of Ophthalmology (AGL), The University of Iowa Hospitals and Clinics, Iowa City, Iowa. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street, Suite Scurlock 450, Houston, TX 77030; E-mail: [e-mail] Thomson et al: J Neuro-Ophthalmol 2022; 42: e417-e419 showed bilateral optic disc edema and a few peripapillary flame hemorrhages in both eyes. Laboratory studies revealed anemia with an Hgb of 9.4 g/dL (normal 12–16 g/dL), an elevated erythrocyte sedimentation rate of 156 mm/hr (normal 0–20 mm/hr), and an increased C-reactive protein of 3.15 mg/L (normal #0.8 mg/L). Serum protein electrophoresis showed a kappa light chain of 17.48 mg/L (normal 3.3–19.4 mg/L), a lambda light chain of 4.52 mg/dL (normal 5.71–26.3 mg/L), and a kappa-to-lambda ratio of 3.87 (normal 0.26–1.65). Computerized tomography (CT) of the brain showed stable cerebral ventriculomegaly compared with CT imaging 5 months before. Contrast-enhanced MRI of the brain and orbits revealed bilateral optic nerve sheath enhancement and enhancement of bilateral oculomotor and trigeminal nerves (Fig. 1). Extensive nodular thickening and leptomeningeal enhancement of the cauda equina was noted on contrast-enhanced MRI of the spine (Fig. 2). Lumbar puncture revealed 372 white blood cells (100% plasma cells), with elevated cerebrospinal fluid (CSF) protein of 1,019 mg/dL (normal 15–45 mg/dL), with a normal opening pressure (16 cmH2O). CSF cytology showed numerous cells with plasmacytoid features, and CSF flow cytometry revealed 34% plasma cells with kappa light chain restriction and immunophenotype CD19+, CD38+, CD45+, CD71+, CD138+, CD 102, CD202, CD562, and CD1172. The patient was diagnosed with MyM, treated empirically with intrathecal methotrexate, discharged to hospice care, and had eventually died 6 weeks after the diagnosis. The median age of MM diagnosis is 70 years; however, patients with CNS-MM are often younger (50–60 years old), with up to 25% diagnosed at initial MM presentation (1). Neurological symptoms in CNS-MM include confusion, limb weakness, headache, gait instability, speech impairment, radiculopathies, and cranial nerve palsies. Cranial nerve involvement may lead to neuro-ophthalmic symptoms, such as diplopia or visual disturbances. However, hyperviscosity, hypercalcemia, amyloid deposition, and drug-induced neuropathy are more common causes of neurological symptoms in MM (2). Development of CNSMM after systemic therapy may be related to the lack or poorly understood CNS penetration of myeloma treatments, including lenalidomide (1,4). e417 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. A. Postcontrast T1 axial fat-saturated MRI showing bilateral enhancement of optic nerves and nerve sheaths (arrows). B. Postcontrast T1 axial fat-saturated MRI showing bilateral trigeminal nerve enhancement (arrowheads). Invasion of MM into the CNS most often occurs hematologically and may manifest as intraparenchymal or leptomeningeal lesions, but direct contiguous extension of cranial plasmacytomas also occurs (1). In our patient, infiltrative optic neuropathy was the most likely etiology, given her left RAPD and bilateral optic disc edema with normal opening pressure on lumbar puncture. MyM, also called leptomeningeal myelomatosis or CNS myelomatosis, is FIG. 2. Postcontrast T1 sagittal fat-saturated MRI showing extensive nodular thickening and leptomeningeal enhancement of the cauda equina (arrows). e418 the direct invasion into the meninges, including the optic nerve sheath, by MM (4). The diagnosis of MyM is based on neuroimaging and CSF cytology, so the radiographic finding of leptomeningeal enhancement on contrastenhanced MRI of the head and spine and the presence of CSF clonal plasma cells establish the diagnosis (5). A multicenter retrospective study on patients with CNS-MM by Jurcyzszyn et al found that of the 135 patients who received imaging, 38% had only leptomeningeal involvement, 34% had only one or more intracranial mass lesions, 19% had both, and 9% had neither (3). Although imaging may help establish the diagnosis of MyM, it carries a 10% false-negative rate (3). The gold standard for neoplastic meningitis diagnosis is CSF cytological analysis, and the addition of flow cytometry is particularly useful, especially in instances of low CSF cell counts or ambiguous cell morphology (5). Monoclonal plasma cells expressing CD38/CD138 are found in around 90% of patients with CNS-MM and potentially confirm the diagnosis of MyM. Loss of a neural cell adhesion molecule (CD56) common in CNS-MM has been hypothesized to contribute to its pathogenesis, but this has yet to be confirmed (1,3). CSF paraprotein (e.g., clonal free light chains) can also help in the diagnosis of MyM (1). Although CSF plasma cells in patients with a history of MM are suspicious for CNS-MM, CSF plasma cells are seen in other infiltrative, inflammatory, and infectious diseases. Workup for viral, bacterial, and fungal disease is especially important in immunocompromised patients (4). In addition, absence of plasma cells does not rule out CNS-MM because this may be seen in cases of parenchymal infiltration or isolated dural involvement (3). Currently, there is no standard treatment for CNS-MM or MyM, and the prognosis remains poor. Proposed therapeutic regimens include CNS radiation, intrathecal chemotherapy, and systemic therapy alone or in Thomson et al: J Neuro-Ophthalmol 2022; 42: e417-e419 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence combination (1). Clinicians should be aware of the possibility of MyM in patients with MM, even in the setting of hematologic remission because they may present with neuro-ophthalmic findings, including optic disc edema, ocular motor cranial neuropathy, headache, or visual disturbances. Such presentations may become more frequent as systemic therapies become more effective and patient overall survival improves. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. C. Thomson, M. O. Nakawah, S. Raviskanthan, P. W. Mortensen, and A. G. Lee; b. Acquisition of data: A. C. Thomson, BS, M. O. Nakawah, S. Raviskanthan, P. W. Mortensen, and A. G. Lee; c. Analysis and interpretation of data: A. C. Thomson, BS, M. O. Nakawah, S. Raviskanthan, P. W. Mortensen, and A. G. Lee. Category 2: a. Drafting the manuscript: A. C. Thomson, BS, M. O. Nakawah, S. Raviskanthan, P. W. Mortensen, and A. G. Lee; b. Revising it for intellectual content: A. C. Thomson, BS, M. O. Nakawah, S. Raviskanthan, P. W. Mortensen, and A. G. Lee. Category 3: a. Final approval of the completed manuscript: A. C. Thomson, BS, M. O. Nakawah, S. Raviskanthan, P. W. Mortensen, and A. G. Lee. Thomson et al: J Neuro-Ophthalmol 2022; 42: e417-e419 REFERENCES 1. Egan PA, Elder PT, Deighan WI, O’Connor SJM, Alexander HD. Multiple myeloma with central nervous system relapse. Haematologica. 2020;105:1780–1790. 2. Nieuwenhuizen L, Biesma DH. Central nervous system myelomatosis: review of the literature. Eur J Haematol. 2008;80:1–9. 3. Jurczyszyn A, Grzasko N, Gozzetti A, Czepiel J, Cerase A, Hungria V, E Crusoe, A Silva Dias, R Vij, MA Fiala, J Caers, L Rasche, AK Nooka, S Lonial, DH Vesole, S Philip, S Gangatharan, A Druzd-Sitek, J Walewski, A Corso, F Cocito, MC M Vekemans, E Atilla, M Beksac, X Leleu, J Davila, A Badros, E Aneja, N Abildgaard, E Kastritis, D Fantl, N Schutz, T Pika, A Butrym, M Olszewska-Szopa, L Usnarska-Zubkiewicz, SZ Usmani, H Nahi, CS Chim, C Shustik, K Madry, S Lentzsch, A Swiderska, G Helbig, R Guzicka-Kazimierczak, N Lendvai, A Waage, KT Andersen, H Murakami, S Zweegman, JJ Castillo. Central nervous system involvement by multiple myeloma: a multi-institutional retrospective study of 172 patients in daily clinical practice. Am J Hematol. 2016;91:575–580. 4. Jadeja N, Nalleballe K, Graber J. Pearls & oy-sters: plasma cell meningitis. Neurology. 2016;87:e240–e242. 5. Bommer M, Kull M, Teleanu V, Schwarzwälder P, Feuring-Buske M, Kroenke J, Bunjes D, Langer C. Leptomeningeal myelomatosis: a rare but devastating manifestation of multiple myeloma diagnosed using cytology, flow cytometry, and fluorescent in situ hybridization. Acta Haematol. 2018;139:247–254. e419 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.